Shashi-Pena Syndrome

A number sign (#) is used with this entry because of evidence that Shashi-Pena syndrome (SHAPNS) is caused by heterozygous mutation in the ASXL2 gene (612991) on chromosome 2p23.

Description

Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures (summary by Shashi et al., 2016).

Clinical Features

Shashi et al. (2016) reported 6 unrelated patients ranging in age from 11 months to 31 years with a similar syndromic disorder. All had variable developmental delay noted from early infancy, which was characterized mainly by delayed walking, delayed and poor speech, hypotonia, and behavioral problems such as attention difficulties and autistic features. Intellectual disability was borderline/mild to severe. Many patients had feeding difficulties shortly after birth. All had macrocephaly, and 3 were noted to have large heads at birth. Common dysmorphic features included hypertelorism, arched eyebrows, prominent eyes or proptosis, ptosis, epicanthal folds, broad nasal tip, long face, retrognathia, low-set posteriorly rotated ears, and glabellar nevus flammeus. Two patients had capillary malformations elsewhere on the body, and 4 had deep palmar creases. Additional more variable features included cardiac atrial septal defect (in 3), episodic hypoglycemia (in 3), and skeletal abnormalities, including kyphosis, scoliosis, advanced bone age, decreased bone mineral density, and increased fractures. Three patients had febrile seizures early in childhood, and 1 developed generalized epilepsy at age 21 years. Brain imaging showed increased extraaxial cerebral space, ventriculomegaly, and white matter volume loss in 5 patients, but was normal in the oldest patient. Shashi et al. (2016) noted the phenotypic similarities to Bohring-Opitz syndrome (BOPS; 605039) and Bainbridge-Ropers syndrome (BRPS; 615485), which result from mutations in the ASXL1 (612990) and ASXL3 (615115) genes, respectively.

Molecular Genetics

In 6 unrelated patients with SHAPNS, Shashi et al. (2016) identified 6 different de novo heterozygous truncating mutations in the ASXL2 gene (612991.0001-612991.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Analysis of cells from 3 patients showed that the mutant transcripts were expressed and not subject to nonsense-mediated mRNA decay, providing support for a dominant-negative effect rather than haploinsufficiency. Additional functional studies were not performed. The patients were ascertained from several large cohorts of patients with neurodevelopmental disorders including a total of 12,030 individuals: statistical analysis indicated that the probability of these 6 de novo truncating mutations occurring by chance in this group was small (1.47 x 10(-10)). Examination of the ExAC browser identified 6 different heterozygous putative loss-of-function ASXL2 variants, which is fewer than expected and suggests that ASXL2 is highly intolerant of loss-of-function variants.

Animal Model

Baskind et al. (2009) found that Asxl2-null mice had reduced body weight, skeletal and vertebral abnormalities, and cardiac dysfunction with congenital heart malformations, enlarged hearts, and premature death. Asxl2 was also ubiquitously expressed in the brain of mouse embryos.

Izawa et al. (2015) found that Asxl2 in mice regulates skeletal, lipid, and glucose homeostasis. Asxl2-null mice developed osteopetrosis, insulin resistance, glucose intolerance, and lipodystrophy. Cellular studies showed that Asxl2 interacted with Pparg (601487) and Rank (603499) to regulate downstream signaling pathways.